'Mito-Bomb': a novel mitochondria-targeting nanosystem for ferroptosis-boosted sonodynamic antitumor therapy.

Mitochondria play an important role in regulating tumor cell death and metabolism so that they can be potential therapeutic targets. Sonodynamic therapy (SDT) represents an attractive antitumor method that induces apoptosis by producing highly toxic reactive oxygen species (ROS). Mitochondria-targeting SDT can cause oxidative damage and improve the efficiency of tumor therapy. However, due to the nonselective distribution of nanosystems and the anti-apoptotic mechanism of cancer cells, the therapeutic effect of SDT is not ideal. Therefore, we proposed a novel mitochondria-targeting nanosystem ('Mito-Bomb') for ferroptosis-boosted SDT. Sonosensitizer IR780 and ferroptosis activator RSL-3 were both encapsulated in biocompatible poly(lactic-co-glycolic acid) (PLGA) nanoparticles to form 'Mito-Bomb' (named IRP NPs). IR780 in this nanosystem was used to mediate mitochondria-targeting SDT. RSL-3 inhibited the activity of GPX4 in the antioxidant system to induce ferroptosis of tumor cells, which could rewire tumor metabolism and make tumor cells extremely sensitive to SDT-induced apoptosis. Notably, we also found that RSL-3 can inhibit hypoxia inducible factor-1α (HIF-1α) and induce ROS production to improve the efficacy of SDT to synergistically antitumor. RSL-3 was applied as a 'One-Stone-Three-Birds' agent for cooperatively enhanced SDT against triple-negative breast cancer. This study presented the first example of RSL-3 boosting mitochondria-targeting SDT as a ferroptosis activator. The 'Mito-Bomb' biocompatible nanosystem was expected to become an innovative tumor treatment method and clinical transformation.

Biomimetic metal-organic frameworks navigated biological bombs for efficient lung cancer therapy.

The rising risk of lung cancer has become a primary global concern with high mortality and mobility. Presently, clinically used anticancer drugs show limited efficacy and significant side effects. A new generation of anticancer weapons is in great demand for lung cancer therapy. Herein, we have developed a novel style of biomimetic zeolitic imidazolate framework-8 (ZIF-8) based on the merits of cell membranes derived from human bone marrow mesenchymal stem cells (hBMSCs), which can navigate biological bombs herpes simplex virus type I thymidine kinase-encoded plasmids (pHSVtk) and ganciclovir (GCV) to treat lung cancer. The biological bomb-loaded structure can kill transfected lung cancer cells and neighboring lung cancer cells through the "bystander effect," which induces efficient suppression of lung cancer both in vitro and in vivo. The biomimetic nanoparticles show an enhanced circulation lifetime and drug accumulation in the tumor tissues and significantly inhibit the tumors. We have developed a straightforward approach to deliver biological bombs with biomimetic metal-organic frameworks for efficient lung cancer therapy. To the best of our knowledge, this is the first report of such a strategy for lung cancer therapy.

An NIR-II Photothermally Triggered "Oxygen Bomb" for Hypoxic Tumor Programmed Cascade Therapy.

Hypoxia, as a characteristic feature of solid tumors, has a close relationship with tumor resistance to photodynamic therapy (PDT) and chemotherapy. Perfluorocarbon (PFC) is reported to relieve hypoxic in solid tumors by acting as an oxygen carrier via several nanostructures. However, the oxygen delivery process is mostly driven by a concentration gradient, which is uncontrollable. Herein, a photothermally controlled "oxygen bomb" PSPP-Au980 -D is designed by encapsulating a PFC core within a functionalized bilayer polymer shell. Near-infrared second window photothermal agent gold nanorods with excellent photo-to-heat energy-conversion ability are fabricated on the surface of the polymer shell via an innovative modified two-step seedless ex situ growth process to thermally trigger O2  release. Then, a programmed cascade therapy strategy is customized for hypoxic orthotopic pancreatic cancer. First, PSPP-Au980 -D is irradiated by a 980 nm laser to photothermally trigger O2  infusing into the hypoxic tumor microenvironment, which is accompanied by local hyperemia and doxorubicin release. Subsequently, a 680 nm laser is used to generate singlet oxygen in the oxygenated tumor microenvironment for PDT. This choreographed programmed cascade therapy strategy will provide a new route for suppressing hypoxic tumor growth under mild conditions based on controllable and effective oxygen release.

Greek Fire, Poison Arrows, and Scorpion Bombs: How Tumor Cells Defend Against the Siege Weapons of Cytotoxic T Lymphocytes.

CD8+ cytotoxic T lymphocytes (CTLs) are the main cellular effectors of the adaptive immune response against cancer cells, which in turn have evolved sophisticated cellular defense mechanisms to withstand CTL attack. Herein we provide a critical review of the pertinent literature on early and late attack/defense events taking place at the CTL/target cell lytic synapse. We examine the earliest steps of CTL-mediated cytotoxicity ("the poison arrows") elicited within seconds of CTL/target cell encounter, which face commensurately rapid synaptic repair mechanisms on the tumor cell side, providing the first formidable barrier to CTL attack. We examine how breach of this first defensive barrier unleashes the inextinguishable "Greek fire" in the form of granzymes whose broad cytotoxic potential is linked to activation of cell death executioners, injury of vital organelles, and destruction of intracellular homeostasis. Herein tumor cells deploy slower but no less sophisticated defensive mechanisms in the form of enhanced autophagy, increased reparative capacity, and dysregulation of cell death pathways. We discuss how the newly discovered supra-molecular attack particles (SMAPs, the "scorpion bombs"), seek to overcome the robust defensive mechanisms that confer tumor cell resistance. Finally, we discuss the implications of the aforementioned attack/defense mechanisms on the induction of regulated cell death (RCD), and how different contemporary RCD modalities (including apoptosis, pyroptosis, and ferroptosis) may have profound implications for immunotherapy. Thus, we propose that understanding and targeting multiple steps of the attack/defense process will be instrumental to enhance the efficacy of CTL anti-tumor activity and meet the outstanding challenges in clinical immunotherapy.

Robotically applied hemostatic clamping for care-under-fire: harnessing bomb robots for hemorrhage control.

BACKGROUND: Early hemorrhage control after interpersonal violence is the most urgent requirement to preserve life and is now recognized as a responsibility of law enforcement. Although earlier entry of first responders is advocated, many shooting scenes remain unsafe for humans, necessitating first responses conducted by robots. Thus, robotic hemorrhage control warrants study as a care-under-fire treatment option. METHODS: Two bomb disposal robots (Wolverine and Dragon Runner) were retrofitted with hemostatic wound clamps. The robots' ability to apply a wound clamp to a simulated extremity exsanguination while controlled by 4 experienced operators was tested. The operators were randomly assigned to perform 10 trials using 1 robot each. A third surveillance robot (Stair Climber) provided further visualization for the operators. We assessed the success rate of the application of the wound clamp to the simulated wound, the time to application of the wound clamp and the amount of fluid loss. We also assessed the operators' efforts to apply the wound clamp after an initial attempt was unsuccessful or after the wound clamp was dropped. RESULTS: Remote robotic application of a wound clamp was demonstrated to be feasible, with complete cessation of simulated bleeding in 60% of applications. This finding was consistent across all operators and both robots. There was no difference in the success rates with the 2 robots (p = 1.00). However, there were differences in fluid loss (p = 0.004) and application time (p < 0.001), with the larger (Wolverine) robot being faster and losing less fluid. CONCLUSION: Law enforcement tactical robots were consistently able to provide partial to complete hemorrhage control in a simulated extremity exsanguination. Consideration should be given to using this approach in care-under-fire and care-behind-the-barricade scenarios as well as further developing the technology and doctrine for robotic hemorrhage control.

Thoracoabdominal injuries after a bomb explosion: blast injuries and their clinical effects.

PURPOSE: To report the types and effects of injuries to the thoracoabdominal region caused by blast and emphasize the importance of the early detection of primary blast injuries. METHODS: Of the 98 patients injured as a result of a bomb explosion, 31 with thoracoabdominal injuries were included in the study. The demographic and laboratory data, operations performed, and radiological findings were obtained from the electronic records of the patients. The injuries caused by the explosion were divided into four categories as primary, secondary, tertiary, and quaternary. The patients with a new injury severity score (NISS) of ≥ 16 were considered to have critical injuries. RESULTS: While mortality developed in 16 (51.6%) of 31 patients included in the study, 15 (48.4%) were discharged after treatment. The mean ages of the patients in the mortality and survivor groups were 29.6 ± 4.5 and 31.1 ± 10.7 years, respectively (p > 0.005). When the two groups were examined, the rate of hypovolemic shock and NISS score were significantly higher in the mortality group (p = 0.001 and p < 0.001, respectively) and the pH of the patients in the mortality group was more acidic (7.18 ± 0.13 vs. 7.34 ± 0.13, p = 0.002). One patient in the survivor group required surgery after the explosion due to missed primary blast injuries. CONCLUSIONS: To make the best use of resources in terrorist attacks and mass casualties that place a huge burden on health systems, it is important to evaluate patients with the highest index of suspicion for concealed blast injuries in terms of hospitalization and observation. In addition, health systems need to develop a cost-effective strategy considering the possibility of delayed-onset blast injuries.

Estimation of radiation-induced health hazards from a "dirty bomb" attack with radiocesium under different assault and rescue conditions.

In the case of a terrorist attack by a "dirty bomb", blast injuries, external irradiation and the incorporation of radioactivity are to be expected. Departing from information about the radiological attack scenario with cesium-137 in the U.S. National Scenario Planning Guide, we estimated the radiological doses absorbed. Similar calculations were performed for a smaller plume size and a detonation in a subway. For conditions as described in the U.S. scenario, the committed effective dose amounted to a maximum of 848 mSv, even for very unfavorable conditions. Red bone marrow equivalent doses are insufficient to induce acute radiation sickness (ARS). In the case of a smaller plume size, the ARS threshold may be exceeded in some cases. In a subway bombing, doses are much higher and the occurrence of ARS should be expected. The health hazards from a dirty bomb attack will depend on the location and the explosive device. The derived Haddon matrix indicates that preparing for such an event includes education of all the medical staff about radiation effects, the time lines of radiation damages and the treatment priorities. Further determinants of the outcome include rapid evacuation even from difficult locations, the availability of a specific triage tool to rapidly identify victims at risk for ARS, the availability of an antidote stockpile and dedicated hospital beds to treat seriously irradiated victims.

Bomb blast: imaging findings, treatment and clinical course of extremity traumas.

BACKGROUND: To describe the severity and types of blast-related extremity injuries and the presence of accompanying vascular injuries (VI) and amputation, and to identify the associated factors affecting the treatment management and clinical course. METHODS: The study included 101 patients with extremity injuries caused by a bomb explosion. The radiographs and computed tomography angiographies of the patients were evaluated in terms of injury patterns, presence of penetrating fragments and fractures, and localization (upper or lower extremity) and type (open or closed) of injury. The Gustilo-Anderson classification was used for open fractures. According to their severity, open fractures classified as types 1 and 2 were included in Group 1 and those classified as type 3A, 3B and 3C in Group 2. RESULTS: As a result of blast exposure, 101 (57.7%) patients had extremity injuries, of which 76 (75.2%) presented with at least one fracture. Of the total of 103 fractures, nine (8.8%) were closed and 94 (91.2%) were open. Thirty-eight (40.4%) of the open fractures were located in the upper extremities, and 56 (59.6%) in the lower extremities and pelvis. Open fractures were most frequently localized in the femur (n = 20; 21.2%), followed by the tibia (n = 18; 19.1%). The majority of patients with open fractures were in Group 1 (71.4%). The duration of hospital stay was longer in Group 2 (12.1 ± 5.8 vs. 6.3 ± 6.7 days, p <  0.0001, respectively). Mortality among patients in Group 2 (45.0%) was significantly higher than in Group 1 (8.0%) (p <  0.0001). Similarly, the injury severity score (ISS) was higher in Group 2 (median 20 vs. 9, p <  0.0001). VI was present in 13 (12.9%) of all patients, and amputation in seven (7.9%). CONCLUSION: The presence of severe open fractures, VI, and high ISS score can be considered as important factors that increase morbidity and mortality. In extremity traumas, through the secondary blast mechanism, contaminated-fragmented tissue injuries occur. Therefore, we believe that it will be beneficial to apply damage control surgery in places with low socioeconomic level and poor hygienic conditions.

Blast-Induced Traumatic Brain Injuries: Experience from the Deadliest Double Suicide Bombing Attack in Iraq.

INTRODUCTION: Blast-induced traumatic brain injuries (bTBIs) are increasingly frequent in civilian settings. We present the first study of individuals with bTBI in Iraq. The study focuses on one of the deadliest suicide car bomb attacks in Iraq and uses it to show the devastating nature of bTBIs. METHODS: This study was conducted at the Neurosurgery Teaching Hospital in Baghdad, Iraq. A retrospective chart analysis of patients with bTBI admitted to the Neurosurgery Teaching Hospital was performed. Measured parameters included patients' demographics, initial presentation, injury patterns, hospital course, surgical management, and outcomes. RESULTS: A total of 75 patients with bTBI were included in this study, 19 of whom died in the emergency room. The remaining 56 patients were admitted to the hospital. Of those patients, 68.6% (n = 39) underwent surgery, and 30.4% were managed conservatively. A modified, tailored triaging system was implemented. All surgery was guided by the principles of damage control neurosurgery. In addition, 76.9% and 46.2% of patients underwent corticectomy and decompressive craniectomy, respectively. Dural venous sinus repair was performed in 17.9% of patients, and 30.7% of the operations entailed additional steps to control major (arterial) cerebrovascular bleeding. The net bTBI-related complication rate was 76%. The total mortality was 48%. Of survivors, 10.7% (n = 8) were discharged with a severe disability. Overall, good outcomes were achieved in 41.3% of the patients. CONCLUSIONS: This study sheds light on the devastating nature of bTBIs. Neurosurgeons worldwide need to be mindful of the unique triaging, diagnostic, and management requirements of these injuries.

Successful Treatment of Major Abdominal Trauma in a 9-year-old Male due to Bomb Explosion.

The present case report describes a pediatric patient that sustained and survived major abdominal trauma due to an open-air explosion during the Syrian civil war. A 9-year-old male patient was brought to our hospital's paediatric emergency department after a bomb explosion that occurred 8 hours prior to presentation. The patient had a severe flap-like skin defect that extended from the below the umbilicus to the right femur. The defect was embedded with multiple stones, plastic, and soil fragments of varying size. Debridement of the anterior abdominal wall was performed, followed by exploratory laparotomy. Multiple sites of perforation of the small bowel were resected, and anastomosis was performed. Vacuum-assisted closure (VAC) was applied to the large wound area. The VAC dressing was changed every 3 days. Granulation tissue developed post-operatively after 26 days and the defect was repaired using skin grafts harvested from the patient's left leg. The patient was considered fully recovered and was discharged 34 days post-surgery. The presented case shows that despite the severity of the patient's major abdominal injuries, rapid wound debridement, exploratory laparotomy, VAC therapy and a multidisciplinary approach are crucial in preventing death and achieving a full recovery.

The explosive trinitrotoluene (TNT) induces gene expression of carbonyl reductase in the blue mussel (Mytilus spp.): a new promising biomarker for sea dumped war relicts?

Millions of tons of all kind of munitions, including mines, bombs and torpedoes have been dumped after World War II in the marine environment and do now pose a new threat to the seas worldwide. Beside the acute risk of unwanted detonation, there is a chronic risk of contamination, because the metal vessels corrode and the toxic and carcinogenic explosives (trinitrotoluene (TNT) and metabolites) leak into the environment. While the mechanism of toxicity and carcinogenicity of TNT and its derivatives occurs through its capability of inducing oxidative stress in the target biota, we had the idea if TNT can induce the gene expression of carbonyl reductase in blue mussels. Carbonyl reductases are members of the short-chain dehydrogenase/reductase (SDR) superfamily. They metabolize xenobiotics bearing carbonyl functions, but also endogenous signal molecules such as steroid hormones, prostaglandins, biogenic amines, as well as sugar and lipid peroxidation derived reactive carbonyls, the latter providing a defence mechanism against oxidative stress and reactive oxygen species (ROS). Here, we identified and cloned the gene coding for carbonyl reductase from the blue mussel Mytilus spp. by a bioinformatics approach. In both laboratory and field studies, we could show that TNT induces a strong and concentration-dependent induction of gene expression of carbonyl reductase in the blue mussel. Carbonyl reductase may thus serve as a biomarker for TNT exposure on a molecular level which is useful to detect TNT contaminations in the environment and to perform a risk assessment both for the ecosphere and the human seafood consumer.

Missile War Injuries of the Craniofacial Region.

Many factors govern the nature, severity, and outcome of missile war injuries and associated soft tissue damages. Managements of primary phase and trauma care have improved significantly. Many of these injured victims survived and require immediate care for primary phase management. Secondary phase was achieved by reconstruction of soft tissue by local, regional flaps, and bony defect by bone grafting.There is no consensus on timing of treatment of bone and soft tissue of missile war injuries.Currently, in Iraq, anti-government's protestors' movement for the last 3 months mainly unemployed young people demanding for human rights has resettled in 22,000 people being injured. This includes more than 600 young men who were assassinated by unknown killers through confrontation with security and police men using tear gas canisters and sound bombs. The demonstrators used mini cars (Tuck Tuck) for attacking policemen and security people and used them for transferring injured demonstrators as ambulance to a special tent in the Tahrir Square for receiving first aid.

Head and neck injuries after a bomb explosion: Diagnostic findings and treatment approaches.

OBJECTIVE: To identify the types and severity of head, face and neck (HFN) injuries, which occurred as a result of a bomb explosion and reached serious life-threatening levels, using radiological imaging methods, and to discuss the options of treatment at the time of presentation. METHODS: Of the 16 patients brought to the emergency department, 14 with HFN injuries were included in the study. Computed tomography (CT) and radiography scans were performed at the time of presentation in all patients, except for one. The injuries were divided into three groups according to their localization as head, face, and neck. RESULTS: A subgaleal hematoma was seen in 10 of 11 (78.5%) patients with head injuries. Eight (57.1%) of nine patients with facial injury had fractures and/or ocular injury in the orbital wall, and seven (50%) patients had maxillofacial bone fractures. Among ocular trauma cases, open-globe injuries were detected in three patients (21.4%), closed-globe in two (14.2%), and both types in three (21.4%). Of the five (35.7%) patients with secondary blast injuries in the neck, three (21.4%) had laryngeal trauma (Zone 2) due to shrapnel, localized in the false vocal cord, epiglottis, and thyrohyoid membrane, respectively. Emergency surgery was performed on a patient with a specific laryngeal injury. CONCLUSION: We consider that in patients presenting to the emergency department with blast HFN injuries, after providing airway patency and hemodynamic stability, CT and CT angiography should be performed because these modalities guide the treatment accurately and promptly.

Peacekeepers suffered combat-related injuries in Mali: a retrospective, descriptive study.

PURPOSE: To describe the combat-related injuries cured by Chinese Level 2 medical treatment facility (CHN L2) in Mali from 1 March 2016 to 1 March 2018, including type of weapon, mortality, nature of injuries, degree and location of injuries and surgical procedures. METHODS : A retrospective, descriptive study of 176 injured cases that met the terrorist attacks was conducted. The medical data were collected by an electronic database system. All collected data were entered into an Excel spreadsheet for calculation. RESULTS: We found that improvised explosive devices (114/176, 65%) were the most commonly used weapons of attack in Mali. 68.75% of the injuries (121/176) were classified as 'minor injuries according to Abbreviated Injury Scale score. As one patient may suffer multiple injuries, each location and nature of injuries was counted separately. Surface injuries were the top (116/197, 58.88%), followed by orthopaedic injuries (52/197, 26.39%) and internal injuries (29/197, 14.72%). The extremities were the most frequently injured body parts (144/197, 73.09%). We operated 175 surgeries to deal with the 176 combat-related injuries, which accounted for 40.05% of all 437 surgeries. The surgical debridement to remove fragments of explosive was the most frequently performed surgery. We also admitted 20 cases (18/176, 34%) into intensive care unit and transferred 40 cases to Level 3 medical facility. CONCLUSION : Peacekeepers taking protective measures for head and trunk frequently got surface injuries. And their unprotected extremities often got injured. The fragment removal was the top surgery and the damage control surgery was the highly technical nature surgery we performed. Chinese military should offer advanced surgical training course to military surgeons who carry out overseas operations.

Military assistance to the civil authority: medical liaison with the Manchester clinicians after the Arena bombing.

UK Defence Medical Services' personnel have experienced an intense exposure to patients injured during war over the last decade and a half. As some bitter lessons of war surgery were relearned and innovative practices introduced, outcomes for patients impr oved consistently as experience accumulated. The repository of many of the enduring lessons learnt at the Role 4 echelon of care remain at the Queen Elizabeth Hospital Birmingham (QEHB), with the National Health Service and Defence Medical Services personnel who treated the returning casualties. On 22 May 2017, a terrorist detonated an improvised explosive device at the Manchester Arena, killing 22 and wounding 159 people. In the aftermath of the event, QEHB was requested to provide support to the Manchester clinicians and teleconferencing and then two clinical visits were arranged. This short report describes the nature of the visits, outlines the principles of Military Aid to the Civil Authority and looks to the future role of the Defence Medical Services in planning and response to UK terrorism events.

Is Kragujevac city still a "hot spot" area, twenty years after the bombing?

After NATO bombing of Serbia in 1999, UNEP has identified Kragujevac as one of the four heavily polluted environmental "hot spots". Damaging of industrial and military targets caused the release of substantial amounts of hazardous chemical substances into the environment. This study was conducted in order to access the exposure of residents of Kragujevac city to persistent soil pollutants, twenty years after NATO air campaign. The paper reports the results of measuring radionuclides, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and heavy metals (As, Cd, Co, Cr, Cu, Mn, Ni, Pb, Zn, and Hg) in soil samples collected from two depths (0-15 cm and 15-30 cm) at 30 locations along the riverbank of the Lepenica River. The average specific activities of 226Ra, 232Th, 40K and 137Cs were comparable to average worldwide values; excess lifetime cancer risk (ELCR) from natural radionuclides ranged from 1.1·10-4 to 3.3·10-4. The measured concentrations of As, Co, Cr, Cu, and Ni exceeded the limit values in most of the samples. Non-carcinogenic risk (hazard quotient and hazard index) and carcinogenic risk from heavy metals were assessed. Total hazard index was 0.257 and 2.16 for adults and children, respectively. Sum of measured PAHs ranged from 110 to 1026 µg kg-1. Sum of PCBs exceeded the limit value of 20 µg kg-1 in all samples (it ranged from 48.8 to 196.8 µg kg-1), but it was still below the remediation level. The differences between two layers with respect to all measured variables were not statistically significant.